Synthesis of functionalized imidazo[4,5-e]thiazolo[3,2-b]triazines by condensation of imidazo[4,5-e]triazinethiones with DMAD or DEAD and rearrangement to imidazo[4,5-e]thiazolo[2,3-c]triazines

• Alexei N. Izmest’ev,
• Dmitry B. Vinogradov,
• Natalya G. Kolotyrkina,
• Angelina N. Kravchenko and
• Galina A. Gazieva

Beilstein J. Org. Chem. 2021, 17, 1141–1148, doi:10.3762/bjoc.17.87

• ], antituberculosis [2], anti-inflammatory [3][4], anticancer [5], antidiabetic [6][7], and antiviral activities [8]. A significant number of biologically active thiazolidines amount to their heteroannelated derivatives, namely, condensed thiazolo[3,2-a]pyrimidines [9] and thiazolo[3,2-b]-1,2,4-triazoles [10], as

Synthetic accesses to biguanide compounds

• Oleksandr Grytsai,
• Cyril Ronco and
• Rachid Benhida

Beilstein J. Org. Chem. 2021, 17, 1001–1040, doi:10.3762/bjoc.17.82

• ], superbases [6], and as ligands for metal complexation [7]. In organic synthesis, biguanides are precursors to several heterocycles [1] such as 1,3,5-triazines, pyrimidines, boron heterocycles, and benzo[f]quinazolines. The application of biguanides as catalysts has been reported mostly for the

Beyond ribose and phosphate: Selected nucleic acid modifications for structure–function investigations and therapeutic applications

• Christopher Liczner,
• Kieran Duke,
• Gabrielle Juneau,
• Martin Egli and
• Christopher J. Wilds

Beilstein J. Org. Chem. 2021, 17, 908–931, doi:10.3762/bjoc.17.76

• destabilization of the duplex, prompting its development. The synthesis of 2'-O-MOE-modified ribonucleosides was first described in 1995 [116]. Since then, two practical strategies have been developed for synthesizing 2'-O-MOE ribonucleosides. For pyrimidines, this involves treating 2,2'-anhydrouridine with

• -Arabinonucleosides of pyrimidines can be prepared from 2,2'-anydronucleosides [174] and purines from approaches which include condensation of the nucleobase with 2,3,5-tri-O-benzyl-ᴅ-arabinofuranosyl chloride [175]. The 2'-fluoro-β-ᴅ-arabinofuranose nucleosides can be prepared by coupling of the nucleobase with 3,5

Microwave-assisted multicomponent reactions in heterocyclic chemistry and mechanistic aspects

• Shivani Gulati,
• Stephy Elza John and
• Nagula Shankaraiah

Beilstein J. Org. Chem. 2021, 17, 819–865, doi:10.3762/bjoc.17.71

• phenanthroline. 6 Pyrimidines/fused pyrimidines 6.1 Pyrimidines Pyrimidines are six-membered aromatic heterocycles containing two nitrogen atoms at positions 1 and 3. These are an important class of compounds depicting a wide range of biological activities such as COX inhibitors, anti-inflammatory, anticancer

• 78 (Scheme 29). 6.2 Fused pyrimidines Fused pyrimidines represent an important class of heterocycles with potential biological activities such as antidiabetic (79), antiviral (80), anti-inflammatory (81, 82), anticancer (83), antibacterial (84) and antiplatelet (85) [75][76][77][78][79] with an

• advantage of the synergistic action of the two pharmacophores fused (Figure 7). 6.2.1 Pyrrolo[2,3-d]pyrimidines: Bhuyan and co-workers [80] reported an efficient MWA three-component reaction between N,N-disubstituted-6-aminouracil 86, arylglyoxal monohydrate 33, and amines 32 in AcOH resulting in the

Synthetic reactions driven by electron-donor–acceptor (EDA) complexes

• Zhonglie Yang,
• Yutong Liu,
• Kun Cao,
• Xiaobin Zhang,
• Hezhong Jiang and
• Jiahong Li

Beilstein J. Org. Chem. 2021, 17, 771–799, doi:10.3762/bjoc.17.67

• -bond adduct. The first light-promoted three-component reaction has been realized by a halogen-bond adduct, forming perfluoroalkylated pyrimidines 26 (Scheme 8). A variety of perfluorinated chains were assembled with methylene compounds and guanidines or amidines, giving the corresponding

• perfluoroalkylated pyrimidines in good to excellent yield. In 2017, Chen and colleagues [34] prepared the phenanthridine derivative 29 with CFL (25 W) irradiation of a solution containing 27, perfluoroalkyl iodide 28, amine additive N,N,N´,N´-tetraethylethylenediamine (TEEDA) in THF (Scheme 9). TEEDA and

• perfluoroalkylated pyrimidines 26 initiated by an EDA complex. Synthesis of phenanthridine derivative 29 initiated by an EDA complex. Synthesis of cis-tetrahydroquinoline derivative 32 initiated by an EDA complex. Mechanism of the synthesis of cis-tetrahydroquinoline derivative 32. Synthesis of phenanthridine

1,2,3-Triazoles as leaving groups: S_NAr reactions of 2,6-bistriazolylpurines with O- and C-nucleophiles

• Dace Cīrule,
• Irina Novosjolova,
• Ērika Bizdēna and
• Māris Turks

Beilstein J. Org. Chem. 2021, 17, 410–419, doi:10.3762/bjoc.17.37

• deprotonated acetylacetone and diphenylmethane. Even there are reports on SNAr reactions of acetylacetone with purines and pyrimidines [56][80], in our hands only polymerization of acetylacetone was observed. On the other hand, the diphenylmethane anion (pKa 32; DMSO [81]) apparently is too basic and

Facile preparation and conversion of 4,4,4-trifluorobut-2-yn-1-ones to aromatic and heteroaromatic compounds

• Takashi Yamazaki,
• Yoh Nakajima,
• Minato Iida and
• Tomoko Kawasaki-Takasuka

Beilstein J. Org. Chem. 2021, 17, 132–138, doi:10.3762/bjoc.17.14

• -ones by the oxidation of the readily accessible corresponding propargylic alcohols as well as their utilization as Michael acceptors for the construction of aromatic and heteroaromatic compounds are reported. Keywords: CF3-containing propargylic alcohols; CF3-containing ynones; oxidation; pyrimidines

• -(trifluoromethyl)pyrimidines (N-nucleophiles), both in a concise fashion, with the full details, including the preparation of 2, being reported herein. Results and Discussion Investigations on the reaction conditions were carried out for the oxidation of propargylic alcohols 1, which were readily accessible by our

• 6aa [37][38][39][40] and 6ba [37][38][41][42], it is noteworthy to realize the construction of relatively rare pyrimidines in a concise fashion via the ynones 2 with a CF3 group. Conclusion As described above, we succeeded in the construction of 4,4,4-trifluorobut-2-yn-1-ones 2 by way of a convenient

Chan–Evans–Lam N1-(het)arylation and N1-alkеnylation of 4-fluoroalkylpyrimidin-2(1H)-ones

• Viktor M. Tkachuk,
• Oleh O. Lukianov,
• Mykhailo V. Vovk,
• Isabelle Gillaizeau and
• Volodymyr A. Sukach

Beilstein J. Org. Chem. 2020, 16, 2304–2313, doi:10.3762/bjoc.16.191

• corresponding pyrimidines. An efficient C–N bond-forming process is also observed by using boronic acid pinacol esters as coupling partners in the presence of Cu(II) acetate and boric acid. The 4-fluoroalkyl group on the pyrimidine ring significantly assists in the formation of the target N1-substituted

Synthesis of 3(2)-phosphonylated thiazolo[3,2-a]oxopyrimidines

• Ksenia I. Kaskevich,
• Anastasia A. Babushkina,
• Vladislav V. Gurzhiy,
• Dmitrij M. Egorov,
• Nataly I. Svintsitskaya and
• Albina V. Dogadina

Beilstein J. Org. Chem. 2020, 16, 1947–1954, doi:10.3762/bjoc.16.161

• , which could be used as an additional approach to estimate the regioselectivity of the reaction. A single example of the use of 13C NMR spectroscopy for unambiguous establishing the structure of thiazolo[3,2-a]pyrimidines obtained was given by Iranian researchers [36], but only for the 5-oxo isomers. In

Regiodivergent synthesis of functionalized pyrimidines and imidazoles through phenacyl azides in deep eutectic solvents

• Paola Vitale,
• Luciana Cicco,
• Ilaria Cellamare,
• Filippo M. Perna,
• Antonio Salomone and
• Vito Capriati

Beilstein J. Org. Chem. 2020, 16, 1915–1923, doi:10.3762/bjoc.16.158

• °C) in the presence or absence of bases (Et3N). Keywords: deep eutectic solvents; imidazoles; phenacyl azides; phenacyl halides; pyrimidines; Introduction In a world with dwindling petroleum resources, the setting up of more and more sustainable routes for the preparation of heterocyclic compounds

• place smoothly using such neoteric solvents (Scheme 1, path a) [16]. Among nitrogen-containing heterocyles, imidazoles and pyrimidines are important structural scaffolds commonly found in natural products [17][18], light-emitting devices [19][20], and pharmacologically active compounds as anticancer

• intramolecular nucleophilic attack to the terminal imino group of 9a, provides cyclized adduct 10a, and finally pyrimidine derivative 7a by aromatization/elimination of NH3. To the best of our knowledge, this is the first one-pot synthesis of functionalized pyrimidines using phenacyl azides as the sole starting

When metal-catalyzed C–H functionalization meets visible-light photocatalysis

• Lucas Guillemard and
• Joanna Wencel-Delord

Beilstein J. Org. Chem. 2020, 16, 1754–1804, doi:10.3762/bjoc.16.147

• , pyrimidines, and oximes (Figure 20). The mild arylation proceeded in good to excellent yields over 20 examples and worked with electron-deficient, electron-rich as well as relatively sterically hindered arylating reagents. The mechanism proposed by the authors is presented in Figure 21. First, the DG-assisted

Design and synthesis of diazine-based panobinostat analogues for HDAC8 inhibition

• Sivaraman Balasubramaniam,
• Sajith Vijayan,
• Liam V. Goldman,
• Xavier A. May,
• Kyra Dodson,
• Sweta Adhikari,
• Fatima Rivas,
• Davita L. Watkins and
• Shana V. Stoddard

Beilstein J. Org. Chem. 2020, 16, 628–637, doi:10.3762/bjoc.16.59

• hydroxamic moieties [13][14][15], the non-availability of the central core modification stimulated our interest toward altering the central core to evaluate efficacy. We found particular interest in the replacement of the phenyl ring with diazine cores (pyridazines, pyrimidines and pyrazines) as their

Synthesis of 4-amino-5-fluoropyrimidines and 5-amino-4-fluoropyrazoles from a β-fluoroenolate salt

• Tobias Lucas,
• Jule-Philipp Dietz and
• Till Opatz

Beilstein J. Org. Chem. 2020, 16, 445–450, doi:10.3762/bjoc.16.41

• Tobias Lucas Jule-Philipp Dietz Till Opatz Institute of Organic Chemistry, Johannes Gutenberg-University, Duesbergweg 10–14, 55128 Mainz, Germany 10.3762/bjoc.16.41 Abstract A synthesis of fluorinated pyrimidines under mild conditions from amidine hydrochlorides and the recently described

• heterocycles; fluorine; pyrazoles; pyrimidines; Introduction Due to its extremely widespread application in virtually all areas of synthetic organic chemistry, fluorine is considered a “magic” element. It confers metabolic stability and other unique properties to organic molecules and a large fraction of

• stage [15][16][17][18][19]. Fluorinated pyrimidines, pyrimidine analogues and pyrazoles [20][21] play a prominent role in several clinically important pharmaceuticals [22][23][24][25]. These compounds act against HIV or HIV-related diseases [26], such as opportunistic fungal infections, and represent

Ultrasonic-assisted unusual four-component synthesis of 7-azolylamino-4,5,6,7-tetrahydroazolo[1,5-a]pyrimidines

• Yana I. Sakhno,
• Maryna V. Murlykina,
• Oleksandr I. Zbruyev,
• Anton V. Kozyryev,
• Svetlana V. Shishkina,
• Dmytro Sysoiev,
• Vladimir I. Musatov,
• Sergey M. Desenko and
• Valentyn A. Chebanov

Beilstein J. Org. Chem. 2020, 16, 281–289, doi:10.3762/bjoc.16.27

• 7-azolylaminotetrahydroazolo[1,5-a]pyrimidines. Keywords: 5-amino-1H-pyrazole-4-carbonitrile; 3-amino-1,2,4-triazole; 7-azolylaminotetrahydroazolo[1,5-a]pyrimidines; heterocycle; multicomponent reaction; ultrasonication; Introduction Tetrahydropyrimidines are heterocycles of high pharmacological

• -pyrazole-4-carbonitrile with aromatic aldehydes and pyruvic acid or its esters under ultrasonication led to the formation of 4,5,6,7-tetrahydroazolo[1,5-a]pyrimidines 4a–u (Scheme 4) containing an azolylamino substituent in the 7-position via an unusual pseudo four-component reaction, rather than two

• ). In contrast to pyrazolyl-substituted pyrazolo[1,5-a]pyrimidine-7-carboxylic acids 4d–o, triazolyl-substituted derivatives 4p–u were unstable in protic solvents in the presence of water, and especially upon increasing the temperature gradually transformed into 7-hydroxytriazolo[1,5-a]pyrimidines 5a–f

Extension of the 5-alkynyluridine side chain via C–C-bond formation in modified organometallic nucleosides using the Nicholas reaction

• Renata Kaczmarek,
• Dariusz Korczyński,
• James R. Green and
• Roman Dembinski

Beilstein J. Org. Chem. 2020, 16, 1–8, doi:10.3762/bjoc.16.1

• common framework for materials with potent biological properties [6][7][8][9][10]. Modification on this site of the nucleobase usually does not interfere with Watson–Crick base pairing. For example, C-5-modified pyrimidines are well tolerated by commercial polymerases [11][12]. Alkynyl modifications not

A green, economical synthesis of β-ketonitriles and trifunctionalized building blocks from esters and lactones

• Daniel P. Pienaar,
• Kamogelo R. Butsi,
• Amanda L. Rousseau and
• Dean Brady

Beilstein J. Org. Chem. 2019, 15, 2930–2935, doi:10.3762/bjoc.15.287

• from lactone to 20% (Scheme 2). Due to the interest in the potential preparation of pyrimidines from β-ketonitriles and guanidine [18], we wanted to test the general applicability of this method for access to a variety of alkyl and aryl-substituted β-ketonitriles (as summarized in Table 1). When we

• the synthesis of glycomimetic products from sugar lactones, and for the synthesis of various pyrimidines. Proposed retrosynthesis of the free diol 1. Preparation of O-unprotected, trifunctionalized synthons from lactones. Preparation of a variety of β-ketonitriles. Supporting Information Supporting

An improved, scalable synthesis of Notum inhibitor LP-922056 using 1-chloro-1,2-benziodoxol-3-one as a superior electrophilic chlorinating agent

• Nicky J. Willis,
• Elliott D. Bayle,
• George Papageorgiou,
• David Steadman,
• Benjamin N. Atkinson,
• William Mahy and
• Paul V. Fish

Beilstein J. Org. Chem. 2019, 15, 2790–2797, doi:10.3762/bjoc.15.271

• air- and moisture-stable. The scope of published substrates includes chlorination of 7H-pyrrolo[2,3-d]pyrimidines and we wished to see if we could extend the scope to include sulphur containing heterocycles such as thieno[3,2-d]pyrimidines (e.g., 6). It was also important to explore if 12 would

In water multicomponent synthesis of low-molecular-mass 4,7-dihydrotetrazolo[1,5-a]pyrimidines

• Irina G. Tkachenko,
• Sergey A. Komykhov,
• Vladimir I. Musatov,
• Svitlana V. Shishkina,
• Viktoriya V. Dyakonenko,
• Vladimir N. Shvets,
• Mikhail V. Diachkov,
• Valentyn A. Chebanov and
• Sergey M. Desenko

Beilstein J. Org. Chem. 2019, 15, 2390–2397, doi:10.3762/bjoc.15.231

• -dihydrotetrazolo[1,5-a]pyrimidine derivatives. Under similar conditions using 4,4,4-trifluoroacetoacetic ester 5-hydroxy-4,5,6,7-tetrahydrotetrazolo[1,5-a]pyrimidines are obtained. The analogous reaction with acetylacetone requires scandium(III) triflate as catalyst. The antioxidant activity of selected compounds

• was assayed with 1,1-diphenyl-2-picrylhydrazyl. Keywords: 5-aminotetrazole; antioxidant activity; 1,3-dicarbonyl compounds; multicomponent synthesis; tetrazolo[1,5-a]pyrimidines; Introduction Tetrazolo[1,5-a]pyrimidines and their partially hydrogenated derivatives are known for their interesting

• biological properties. They have been reported to have anticancer [1], antimicrobial [2][3] and antioxidant [3] activities and to act as inhibitors of hepatitis B virus [4]. The dihydro derivatives of tetrazolo[1,5-a]pyrimidines belong to a bit special kind of dihydropyrimidines due to the strong electron

Recent advances on the transition-metal-catalyzed synthesis of imidazopyridines: an updated coverage

• Gagandeep Kour Reen,
• Ashok Kumar and
• Pratibha Sharma

Beilstein J. Org. Chem. 2019, 15, 1612–1704, doi:10.3762/bjoc.15.165

• halide substituent in the product which was successfully overcome by this protocol along with the synthesis of pyrazines and pyrimidines in high yield (Scheme 3). Furthermore, easy functionalization of the products from the viewpoint of reactive halide made them valuable synthons. Molecular oxygen used

• derivatives have been reported by the group of R. K. Reddy [113]. The protocol offered an open air, ligand- and base-free methodology with an extension towards the synthesis of imidazo[1,2-a]pyrazines/pyrimidines and benzo[d]imidazo[2,1-b]thiazoles. For this reaction, they have synthesized the respective

One-pot activation–alkynylation–cyclization synthesis of 1,5-diacyl-5-hydroxypyrazolines in a consecutive three-component fashion

• Christina Görgen,
• Katharina Boden,
• Guido J. Reiss,
• Walter Frank and
• Thomas J. J. Müller

Beilstein J. Org. Chem. 2019, 15, 1360–1370, doi:10.3762/bjoc.15.136

• ][51][52], pyrimidines [48][49], and 5-acylpyrazoles [48][49]. The latter 5-acylpyrazole arose after work-up from the three-component AA–cyclocondensation synthesis employing Boc-hydrazine as a binucleophilic hydrazide substrate. Based on our attempts to isolate potential 1,5-diacylpyrazole precursors

Steroid diversification by multicomponent reactions

• Leslie Reguera,
• Cecilia I. Attorresi,
• Javier A. Ramírez and
• Daniel G. Rivera

Beilstein J. Org. Chem. 2019, 15, 1236–1256, doi:10.3762/bjoc.15.121

• epiandrosterone acetate, etc., all providing excellent yields of steroidal pyrimidines after 12 h of reaction at 90 °C (Scheme 13). The reaction sequence of this multicomponent protocol comprises the initial formation of the Biginelli product, followed by aromatization under air to furnish the heterocyclic ring

• strong oxidizing Jones reagent, because the oxidizing power of sulfuric acid was not enough to achieve oxidation. Interestingly, the use of microwave irradiation instead of classic heating allowed obtaining the Biginelli product in only 10 min, instead of 12 h as required for the synthesis of pyrimidines

• targeting steroid-fused pyrimidines, Boruah’s group developed a solid-phase MCR between 2-hydroxymethylene-3-ketosteroids, aromatic aldehydes and ammonium acetate [46]. As shown in Scheme 15, the reaction was carried out with steroid 49 and different aldehydes to furnish the set of compounds 50 in good to

The LANCA three-component reaction to highly substituted β-ketoenamides – versatile intermediates for the synthesis of functionalized pyridine, pyrimidine, oxazole and quinoxaline derivatives

• Tilman Lechel,
• Roopender Kumar,
• Mrinal K. Bera,
• Reinhold Zimmer and
• Hans-Ulrich Reissig

Beilstein J. Org. Chem. 2019, 15, 655–678, doi:10.3762/bjoc.15.61

• ammonium salts or with hydroxylamine hydrochloride afford pyrimidines PM or pyrimidine N-oxides PO with a highly flexible substitution pattern in good yields. The functional groups of these heterocycles also allow a variety of subsequent reactions to various pyrimidine derivatives. On the other hand, acid

• reactions are possible. Keywords: allenes; condensations; multicomponent reactions; oxazoles; pyrimidines; quinoxalines; Introduction Multicomponent reactions are known to create unique product skeletons in an atom economic, efficient and time saving fashion. In many cases, compounds bearing functional

• particular heterocyclic compounds. The synthesis of pyrimidines PM, pyrimidine N-oxides PO, oxazoles OX, 1,2-diketones DK and quinoxalines QU starting from β-ketoenamides KE is the topic of the present review. Review Scope of the LANCA three-component synthesis of β-ketoenamides The scope of the LANCA three

Synthesis and fluorescent properties of N(9)-alkylated 2-amino-6-triazolylpurines and 7-deazapurines

• Andrejs Šišuļins,
• Jonas Bucevičius,
• Yu-Ting Tseng,
• Irina Novosjolova,
• Kaspars Traskovskis,
• Ērika Bizdēna,
• Huan-Tsung Chang,
• Sigitas Tumkevičius and
• Māris Turks

Beilstein J. Org. Chem. 2019, 15, 474–489, doi:10.3762/bjoc.15.41

• to increased fluorescence quantum yield (74%) in THF solution. The compounds exhibit low cytotoxicity and as such are useful for the cell labelling studies in the future. Keywords: 7-deazapurines; fluorescence; nucleophilic aromatic substitution; purines; push–pull systems; pyrrolo[2,3-d]pyrimidines

Targeting the Pseudomonas quinolone signal quorum sensing system for the discovery of novel anti-infective pathoblockers

• Christian Schütz and
• Martin Empting

Beilstein J. Org. Chem. 2018, 14, 2627–2645, doi:10.3762/bjoc.14.241

Applications of organocatalysed visible-light photoredox reactions for medicinal chemistry

• Michael K. Bogdos,
• Emmanuel Pinard and
• John A. Murphy

Beilstein J. Org. Chem. 2018, 14, 2035–2064, doi:10.3762/bjoc.14.179

• oxidant (Scheme 22) [67]. Heterocycles in drugs are not only restricted to five-membered rings. Pyridines, pyrazines, pyrimidines, pyridazines are all common functional groups in biologically active compounds. Liu et al. have published the visible light-catalysed oxidation of dihydropyrimidines (DHPMs